Background: The most consistently replicated genetic variants associated with coronary heart disease (CHD) in populations of European descent have been found on chromosome 9p21. Yet there is little known about these associations in ethnic groups of African ancestry. These disease-associated variants are located in a genomic region of unknown function. The purpose of this exploratory study was to examine the allelic frequencies and haplotype structure of single nucleotide polymorphisms (SNPs) for Black and White women with CHD. The authors also sought to explore the relationship between these genetic variants and biomarkers of inflammation. Methods: Using polymerase chain reaction amplification, the authors genotyped 8 SNPs in a 58-kilobase region of chromosome 9p21 in a cohort of women with CHD (n = 91). The authors examined the interethnic relationship between the SNPs and four inflammatory biomarkers (C-reactive protein, intercellular adhesion molecule-1, interleukin-6, and tumor necrosis factor-alpha) using analysis of variance (ANOVA). Results: We found considerable interethnic allelic and haplotype diversity across the 9p21 locus, with only two SNPs in perfect linkage disequilibrium (LD) in both races. A pair of high- and low-risk haplotypes was most common in White women, while about 41% of Blacks carried the risk alleles for three of the eight SNPs the authors examined. The interethnic associations between the SNP genotypes and inflammatory markers were divergent in both direction and magnitude. Conclusions: Our results lend support for the importance of ancestry-specific allelic context when examining variants on chromosome 9p21. Additional work is needed to elucidate the genetic contribution to inflammatory biomarkers for diverse racial groups.
Albert, M.A. ( 2007). Inflammatory biomarkers, race/ethnicity and cardiovascular disease. Nutrition Reviews, 65, S234-238.
2.
Albert, M.A., Pare, G., Morris, A., Rose, L., Buring, J., Ridker, P.M., & Zee, R.Y. ( 2009). Candidate genetic variants in the fibrinogen, methylenetetrahydrofolate reductase, and intercellular adhesion molecule-1 genes and plasma levels of fibrinogen, homocysteine, and intercellular adhesion molecule-1 among various race/ethnic groups: Data from the Women’s Genome Health Study. American Heart Journal, 157, 777-783.
3.
Arnett, D.K., Baird, A.E., Barkley, R.A., Basson, C.T., Boerwinkle, E., Ganesh, S.K., & . . .O’Donnell, C.J. (2007). Relevance of genetics and genomics for prevention and treatment of cardiovascular disease: A scientific statement from the American Heart Association Council on Epidemiology and Prevention, the Stroke Council, and the Functional Genomics and Translational Biology Interdisciplinary Working Group. Circulation, 115, 2878-2901.
4.
Assimes, T., Knowles, J., Basu, A., Iribarren, C., Southwick, A., Tang, H., & . . . Quertermous, T. (2008). Susceptibility locus for clinical and subclinical coronary artery disease at chromosome 9p21 in the multi-ethnic ADVANCE study. Human Molecular Genetics, 17, 2320-2328.
5.
Barrett, J., Fry, B., Maller, J., & Daly, M. ( 2005). Haploview: Analysis and visualization of LD and haplotype maps. Bioinformatics, 21, 263-265.
6.
Beckie, T.M. ( 2006). A behavior change intervention for women in cardiac rehabilitation . Journal of Cardiovascular Nursing, 21, 146-153.
7.
Beckie, T.M., Beckstead, J.W., & Groer, M.W. ( 2010). The influence of cardiac rehabilitation on inflammation and metabolic syndrome in women with coronary heart disease. Journal of Cardiovascular Nursing, 25, 52-60.
8.
Beckie, T.M., Beckstead, J.W., Schocken, D.D., Evans, M.E., & Fletcher, G.F. (2011). The effects of a tailored cardiac rehabilitation program on depressive symptoms in women: A randomized clinical trial. International Journal of Nursing Studies, 48, 3-12.
9.
Beckie, T.M., Mendonca, M.A., Fletcher, G.F., Schocken, D.D., Evans, M.E., & Banks, S.M. ( 2009). Examining the challenges of recruiting women into a cardiac rehabilitation clinical trial. Journal of Cardiopulmonary Rehabilitation and Prevention, 29, 13-21.
10.
Brautbar, A., Ballantyne, C.M., Lawson, K., Nambi, V., Chambless, L., Folsom, A.R., & ... Boerwinkle, E. (2009). Impact of adding a single allele in the 9p21 locus to traditional risk factors on reclassification of coronary heart disease risk and implications for lipid-modifying therapy in the Atherosclerosis Risk in Communities study. Circulation Cardiovascular Genetics , 2, 279-285.
11.
Broadbent, H., Peden, J., Lorkowski, S., Goel, A., Ongen, H., Green, F., & ... Watkins, H. (2008). Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p. Human Molecular Genetics , 17, 806-814.
12.
Carlson, C.S., Eberle, M.A., Rieder, M.J., Yi, Q., Kruglyak, L., & Nickerson, D.A. (2004). Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. American Journal of Human Genetics , 74, 106-120.
13.
Carroll, J.F., Fulda, K.G., Chiapa, A.L., Rodriquez, M., Phelps, D.R., Cardarelli, K.M., & ... Cardarelli, R. (2009). Impact of race/ethnicity on the relationship between visceral fat and inflammatory biomarkers. Obesity , 17, 1420-1427.
14.
Chen, S.N., Ballantyne, C.M., Gotto, A.M. Jr., & Marian, A.J. ( 2009). The 9p21 susceptibility locus for coronary artery disease and the severity of coronary atherosclerosis. BMC Cardiovascular Disorders, 9, 3.
15.
Chen, Z., Qian, Q., Ma, G., Wang, J., Zhang, X., Feng, Y., & ... Yao, Y. (2009). A common variant on chromosome 9p21 affects the risk of early-onset coronary artery disease. Molecular Biology Reports, 36, 889-893.
16.
Cohen, J. ( 1988). Statistical power analysis for the behavioral sciences (3rd ed.). New York, NY: Academic Press.
17.
Cook, N.R., Buring, J.E., & Ridker, P.M. ( 2006). The effect of including C-reactive protein in cardiovascular risk prediction models for women. Annals of Internal Medicine , 145, 21-29.
18.
Dandona, S., Stewart, A.F., Chen, L., Williams, K., So, D., O’Brien, E., & ... Roberts, R. (2010). Gene dosage of the common variant 9p21 predicts severity of coronary artery disease. Journal of the American College of Cardiology, 56, 479-486.
19.
Despres, J.P., & Lemieux, I. ( 2006). Abdominal obesity and metabolic syndrome. Nature, 444, 881-887.
20.
Devlin, B., & Risch, N. ( 1995). A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics, 29, 311-322.
21.
Elliott, P., Chambers, J.C., Zhang, W., Clarke, R., Hopewell, J.C., Peden, J.F., & ... Kooner, J. S. (2009). Genetic loci associated with C-reactive protein levels and risk of coronary heart disease. Journal of the American Medical Association, 302, 37-48.
22.
Ellis, K.L., Pilbrow, A.P., Frampton, C.M., Doughty, R.N., Whalley, G.A., Ellis, C.J., & ... Cameron, V. A. (2010). A common variant at chromosome 9P21.3 is associated with age of onset of coronary disease but not subsequent mortality. Circulation Cardiovascular Genetics, 3, 286-293.
23.
Espinola-Klein, C., Rupprecht, H.J., Bickel, C., Post, F., Genth-Zotz, S., Lackner, K., & ... Blankenberg, S. (2007). Impact of metabolic syndrome on atherosclerotic burden and cardiovascular prognosis. American Journal of Cardiology, 99, 1623-1628.
24.
Feinberg, M.S., Schwartz, R., & Behar, S. ( 2008). Impact of metabolic syndrome in patients with acute coronary syndrome. Advances in Cardiology, 45, 114-126.
25.
Ferro, W., Geada, D., Guevara, Y., Padilla, S., Conde, A., Alvarez, T., & ... Valdes, R. (2010). Prolonged stability of the plantibody HB-01 directed against the hepatitis B surface antigen in cryo-preserved tobacco leaves. Biologicals, 38, 415-419.
26.
Ford, E.S., Giles, W.H., Mokdad, A.H., & Myers, G.L. ( 2004). Distribution and correlates of C-reactive protein concentrations among adult US women. Clinical Chemistry, 50, 574-581.
27.
Gami, A.S., Witt, B.J., Howard, D.E., Erwin, P.J., Gami, L.A., Somers, V.K., & Montori, V.M. ( 2007). Metabolic syndrome and risk of incident cardiovascular events and death: A systematic review and meta-analysis of longitudinal studies . Journal of the American College of Cardiology, 49, 403-414.
28.
Grundy, S.M., Cleeman, J.I., Daniels, S.R., Donato, K.A., Eckel, R.H., Franklin, B.A., & ... Costa, F. ( 2005). Diagnosis and management of the metabolic syndrome: An American Heart Association/ National Heart, Lung, and Blood Institute Scientific Statement. Circulation, 112, 2735-2752.
29.
Grundy, S.M., Cleeman, J.I., Daniels, S.R., Donato, K.A., Eckel, R.H., Franklin, B.A., & ... Costa, F. ( 2006). Diagnosis and management of the metabolic syndrome: An American Heart Association/ National Heart, Lung, and Blood Institute scientific statement. Current Opinion in Cardiology, 21, 1-6.
30.
Helgadottir, A., Thorleifsson, G., Manolescu, A., Gretarsdottir, S., Blondal, T., Jonasdottir, A., & ... Stefansson, K. (2007). A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science, 316, 1491-1493.
31.
Helsel, D.R. ( 2005). More than obvious: Better methods for interpreting nondetect data. Environmental Science and Technology, 39, 419A-423A.
32.
Hinohara, K., Nakajima, T., Takahashi, M., Hohda, S., Sasaoka, T., Nakahara, K., & ... Kimura, A. (2008). Replication of the association between a chromosome 9p21 polymorphism and coronary artery disease in Japanese and Korean populations. Journal of Human Genetics, 53, 357-359.
33.
Horne, B.D., Carlquist, J.F., Muhlestein, J.B., Bair, T.L., & Anderson, J.L. (2008). Association of variation in the chromosome 9p21 locus with myocardial infarction versus chronic coronary artery disease. Circulation Cardiovascular Genetics, 1, 85-92.
34.
Humphries, S.E., Drenos, F., Ken-Dror, G., & Talmud, P.J. ( 2010). Coronary heart disease risk prediction in the era of genome-wide association studies: Current status and what the future holds . Circulation, 121, 2235-2248.
35.
Hyatt, T.C., Phadke, R.P., Hunter, G.R., Bush, N.C., Munoz, A.J., & Gower, B.A. ( 2009). Insulin sensitivity in African-American and White women: Association with inflammation. Obesity, 17, 276-282.
36.
International HapMap Consortium.. (2005). A haplotype map of the human genome. Nature, 437, 1299-1320.
37.
International HapMap Project. (2003). Nature, 426, 789-796.
Karvanen, J., Silander, K., Kee, F., Tiret, L., Salomaa, V., Kuulasmaa, K., & ... Evans, A. ( 2008). The impact of newly identified loci on coronary heart disease, stroke and total mortality in the MORGAM prospective cohorts . Genetic Epidemiology, 33, 237-246.
40.
Kim, H.C., Greenland, P., Rossouw, J.E., Manson, J.E., Cochrane, B.B., Lasser, N.L., & ... Robinson, J.G. (2010). Multimarker prediction of coronary heart disease risk: The Women’s Health Initiative. Journal of the American College of Cardiology, 55, 2080-2091.
41.
Koenig, W., & Khuseyinova, N. (2007). Biomarkers of atherosclerotic plaque instability and rupture. Arteriosclerosis, Thrombosis, and Vascular Biology, 27, 15-26.
42.
Lewontin, R.C. ( 1964). The interaction of selection and linkage. I. General considerations; heterotic models. Genetics, 49, 49-67.
43.
Libby, P. ( 2002). Inflammation in atherosclerosis. Nature , 420, 868-874.
44.
Libby, P., Okamoto, Y., Rocha, V.Z., & Folco, E. ( 2010). Inflammation in atherosclerosis: Transition from theory to practice. Circulation Journal, 74, 213-220.
45.
Maitra, A., Dash, D., John, S., Sannappa, P.R., Das, A.P., Shanker, J., & ... Kakkar, V. V. (2009). A common variant in chromosome 9p21 associated with coronary artery disease in Asian Indians. Journal of Genetics, 88, 113-118.
46.
McEwen, B.S. ( 1998a). Protective and damaging effects of stress mediators . New England Journal of Medicine, 338, 171-179.
47.
McEwen, B.S. ( 1998b). Stress, adaptation, and disease. Allostasis and allostatic load. Annals of the New York Academy of Sciences , 840, 33-44.
48.
McPherson, R. ( 2010). Chromosome 9p21 and coronary artery disease. New England Journal of Medicine, 362, 1736-1737.
49.
McPherson, R., Pertsemlidis, A., Kavaslar, N., Stewart, A., Roberts, R., Cox, D.R., & ... Cohen, J. ( 2007). A common allele on chromosome 9 associated with coronary heart disease. Science, 316, 1488-1491.
50.
Meng, W., Hughes, A.E., Patterson, C.C., Belton, C., Kee, F., & McKeown, P.P. ( 2008). Chromosome 9p21.3 is associated with early-onset coronary heart disease in the Irish population. Disease Markers , 25, 81-85.
51.
Ness, R.B., Haggerty, C.L., Harger, G., & Ferrell, R. ( 2004). Differential distribution of allelic variants in cytokine genes among African Americans and White Americans. American Journal of Epidemiology, 160, 1033-1038.
52.
Newton-Cheh, C., Cook, N.R., VanDenburgh, M., Rimm, E.B., Ridker, P.M., & Albert, C.M. ( 2009). A common variant at 9p21 is associated with sudden and arrhythmic cardiac death. Circulation, 120, 2062-2068.
53.
Novack, V., Cutlip, D.E., Jotkowitz, A., Lieberman, N., & Porath, A. ( 2008). Reduction in sex-based mortality difference with implementation of new cardiology guidelines. American Journal of Medicine , 121, 597-603.
54.
Palomaki, G.E., Melillo, S., & Bradley, L.A. ( 2010). Association between 9p21 genomic markers and heart disease: A meta-analysis. Journal of the American Medical Association , 303, 648-656.
55.
Paynter, N.P., Chasman, D.I., Buring, J.E., Shiffman, D., Cook, N.R., & Ridker, P.M. ( 2009). Cardiovascular disease risk prediction with and without knowledge of genetic variation at chromosome 9p21.3Annals of Internal Medicine, 150, 65-72.
56.
Pischon, T., Hu, F.B., Rexrode, K.M., Girman, C.J., Manson, J.E., & Rimm, E.B. ( 2008). Inflammation, the metabolic syndrome, and risk of coronary heart disease in women and men. Atherosclerosis , 197, 392-399.
57.
Ridker, P.M., Buring, J.E., Cook, N.R., & Rifai, N. ( 2003). C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: An 8-year follow-up of 14 719 initially healthyAmerican women. Circulation, 107, 391-397.
58.
Ridker, P.M., Hennekens, C.H., Buring, J.E., & Rifai, N. ( 2000). C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. New England Journal of Medicine, 342, 836-843.
59.
Roberts, R., Wells, G.A., Stewart, A.F., Dandona, S., & Chen, L. ( 2010). The genome-wide association study - A new era for common polygenic disorders. Journal of Cardiovascular Translational Research, 3, 173-182.
60.
Roy, H., Bhardwaj, S., & Yla-Herttuala, S. (2009). Molecular genetics of atherosclerosis. Human Genetics, 125, 467-491.
61.
Saleheen, D., Alexander, M., Rasheed, A., Wormser, D., Soranzo, N., Hammond, N., & . . . Danesh, J. (2010) Association of the 9p21.3 locus with risk of first-ever myocardial infarction in Pakistanis: Case-control study in South Asia and updated meta-analysis of Europeans. Arteriosclerosis, Thrombosis, and Vascular Biology, 30, 1467-1473.
62.
Samani, N.J., Erdmann, J., Hall, A.S., Hengstenberg, C., Mangino, M., Mayer, B., & . . . Schunkert, H. (2007). Genomewide association analysis of coronary artery disease. New England Journal of Medicine, 357, 443-453.
63.
Samani, N.J., Raitakari, O.T., Sipila, K., Tobin, M.D., Schunkert, H., Juonala, M., & ... Lehtimaki, T. (2008). Coronary artery disease-associated locus on chromosome 9p21 and early markers of atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology, 28, 1679-1683.
64.
Schnabel, R.B., Lunetta, K.L., Larson, M.G., Dupuis, J., Lipinska, I., Rong, J., & . . . Benjamin, E.J. (2009). The relation of genetic and environmental factors to systemic inflammatory biomarker concentrations . Circulation Cardiovascular Genetics, 2, 229-237.
65.
Schuett, H., Luchtefeld, M., Grothusen, C., Grote, K., & Schieffer, B. ( 2009). How much is too much? Interleukin-6 and its signalling in atherosclerosis. Thrombosis and Haemostasis, 102, 215-222.
66.
Schunkert, H., Gotz, A., Braund, P., McGinnis, R., Tregouet, D.A., Mangino, M., & . . . Samani, N.J. (2008). Repeated replication and a prospective meta-analysis of the association between chromosome 9p21.3 and coronary artery disease. Circulation, 117, 1675-1684.
67.
Silander, K., Tang, H., Myles, S., Jakkula, E., Timpson, N., Cavalli-Sforza, L., & . . . Peltonen, L. (2009). Worldwide patterns of haplotype diversity at 9p21.3, a locus associated with type 2 diabetes and coronary heart disease . Genome Medicine, 1, 51.
68.
Stephens, M., & Donnelly, P. ( 2003). A comparison of bayesian methods for haplotype reconstruction from population genotype data. American Journal of Human Genetics , 73, 1162-1169.
69.
Stephens, M., Smith, N.J., & Donnelly, P. ( 2001). A new statistical method for haplotype reconstruction from population data. American Journal of Human Genetics, 68, 978-989.
70.
Van Dyke, A.L., Cote, M.L., Wenzlaff, A.S., Land, S., & Schwartz, A.G. (2009). Cytokine SNPs: Comparison of allele frequencies by race and implications for future studies. Cytokine, 46, 236-244.
71.
Walston, J.D., Fallin, M.D., Cushman, M., Lange, L., Psaty, B., Jenny, N., & . . . Reiner, A. (2007). IL-6 gene variation is associated with IL-6 and C-reactive protein levels but not cardiovascular outcomes in the Cardiovascular Health Study. Human Genetics , 122, 485-494.
72.
Wellcome Trust Case Control Consortium. (2007 ). Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature, 447, 661-678.
73.
Yamada, Y., Ichihara, S., & Nishida, T. ( 2008). Molecular genetics of myocardial infarction. Genomic Medicine, 2, 7-22.
74.
Yan, E., Chen, S., Hong, K., Kim, W.S., Bajpai, A., Treyzon, L., & ... Heber, D. ( 2008). Insulin, hs-CRP, leptin, and adiponectin. An analysis of their relationship to the metabolic syndrome in an obese population with an elevated waist circumference. Metabolic Syndrome and Related Disorders, 6, 64-73.
75.
Zhang, J., Rowe, W.L., Clark, A.G., & Buetow, K.H. ( 2003). Genomewide distribution of high-frequency, completely mismatching SNP haplotype pairs observed to be common across human populations . American Journal of Human Genetics, 73, 1073-1081.
